Parathyroid hormone 1-34 (PTH(1-34)) is a 34 amino acids polypeptide and FDA approved clinical drug for the treatment of osteoporosis and bone disorders. Recently, it was found that PTH(1-34) acts on articular chondrocytes to suppress their terminal differentiation, and it can also suppress papain-induced osteoarthritis (OA) in rats (Chang, J. K., et al., Parathyroid hormone 1-34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats. Arthritis Rheum, 2009. 60(10): p. 3049-60). But, the treatments require the administration of drug once in 3 days, which makes more sufferings and inconvenient for patient undergoing the treatment. Thus, there is a need to develop a new controlled releasing carrier formulation of a parathyroid hormone peptide in order to reduce the patient suffering and that has suitable bioavailability such that therapeutic level can be achieved for effective treatment of PTH related disorders.
In pharmacology, bioavailability (BA) is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.
In recent years, many methods have been investigated for the administration of PTH to the treatment in clinical trials. A recent reported method emphasized the oral administration of PTH(1-34) showed biologically active. However, the bioavailability of PTH is only 5% and 2.1%, in comparison to subcutaneous administration. On the other hand, the pulmonary route has shown 40% and 34% bioavailabilities of PTH(1-34) by means of intratracheal instillation or inhalation of dry powders, respectively. In addition to that for intermittent PTH delivery include programmed administration by osmotic pump and pulsatile transdermal administration. Both of these methods showed equivalent anabolic actions of PTH on bone like subcutaneous administration. Human PTH(1-38) has also shown similar results. There is relatively little work focusing on local delivery of PTH. Notably, these few studies indicated that PTH administered locally via a direct gene delivery which was found to be beneficial in the treatment of bony defects.
PTH(1-34), also called teriparatide, is commercially available in market under the brand name FORTEO® manufactured by Eli Lilly, Indianapolis, Ind., for the treatment of osteoporosis in postmenopausal women with high risk of fracture. This drug is administered by once in daily subcutaneous injection of PTH(1-34) formulations (acetate buffer, mennitol, and m-cresol in water, pH 4). However, many people had adverse response to injections, and thus become non-compliance with the prescribed dosing of the PTH. Therefore, an appropriate drug carrier is required to prolong the injection interval and sustained release of PTH(1-34) over a time period.